The sum of the biological reactions and processes within an organism is effected by proteins, or complexes of proteins with other biomolecules. Determination of a protein's three dimensional structure or fold, is fundamental to elucidating biological form and function. A detailed description of the folding process, the energetics of folding, and the energetics of protein - biomolecule interactions provides valuable insight in understanding the molecular bases of diseases caused by mutant proteins with aberrant functions, and the design of potential targets and gene therapies. There is a large body of evidence which indicates that changes in the hydration state of a protein is a key determinant of the folding process. Using Staphylococcal nuclease as a model system, I propose to study hydration-driven structural changes via a new high pressure X-ray crystallographic technique, and fluorescence and NMR spectroscopy.